1. Description of the Prior Art
Beta-lactam antibiotics, such as penicillin, methicillin, amoxicillin and the like, have been used for many years in battling bacterial infections in humans. After repeated exposure to this type of antibiotic, however, many bacterial strains have become resistant to these antibiotics and now render them ineffective in treating infections. The medical and scientific community believes that bacterial resistance to beta-lactam antibiotics can usually be attributed to the ability of these bacteria to produce beta-lactamase, an enzyme that cleaves the chemical structure of the beta-lactam antibiotics.
Researchers have, therefore, approached this problem by searching for beta-lactamase inhibitors that will prevent the action of beta-lactamase and permit this class of antibiotics to remain active in treating bacterial infections. Some of these beta-lactamase inhibitors are antibacterial; some act synergistically with beta-lactam antibiotics to increase their effectiveness.
For example, U.S. Pat. No. 4,340,539 (Gottstein), entitled "Derivatives of 6-bromo Penicillanic Acid" states that 2-B-chloromethyl-2a-methylpenam-3a-carboxylic acid sulfone and salts and esters thereof are potent inhibitors of beta-lactamases. The patent states that the active derivatives of 6-bromo penicillanic acid, in conjunction with ceforanide and amoxicillin, prevent the destruction of these beta-lactam antibiotics and permit continued antibacterial activity. The active material was demonstrated to have very weak antibacterial activity by itself.
R. Baltzer, et al., in their article "Mutual ProDrugs of B-Lactam Antibiotics and B-Lactamase Inhibitors," J. Antibiotics 33(10), 1183-1192 (1980) describes the combination of a beta-lactam antibiotic with a beta-lactamase inhibitor in a single molecule functioning as a pro-drug for the two active components. A beta-lactamase inhibitor, penicillanic acid sulfone, was combined with ampicillin and mecillinam. The article states that, in humans, these esters are absorbed from the gastrointestinal tract and, after absorption, are hydrolyzed with liberation of the active components.
U.S. Pat. No. 4,377,590 (Myers), entitled "Derivatives of Ampicillin and Amoxicillin with Beta-Lactamase Inhibitors" describes certain antibiotics having beta-lactamase inhibitors. These antibiotics contain a beta-lactam ring, as well as a carboxy group located on either the amino group of ampicillin, the amino group of amoxicillin, or the phenolic hydroxy group of amoxicillin.
European Patent Publication EP 0023 093 A1 (Harbridge), entitled "Pencillanic Acid Derivatives, Their Preparation and Use in Pharmaceutical Compositions" relates to pharmaceutical compositions containing penicillin or cephalosporin. The publication states that a class of penicillanic acid derivatives having antibacterial activity possess the ability to enhance the effectiveness of penicillin and cephalosporins.
British Patent No. 1,573,503 (Cherry, et al.), entitled "Ethers of (2)-hydroxy-ethylidene-clavam-(3)-carboxylic acid--Useful Antibiotics, Beta-lactamase Inhibitors and Intermediates" relates to ethers of clavulanic acid and their salts and esters. These compounds can be utilized as antibiotics or as beta-lactamase inhibitors. The patent states that these compounds have some antibiotic activity and are stable to the action of beta-lactamases. The patent also states that the compounds inhibit beta-lactamase enzymes.
WO 9117995 (Altamura, et al.) describes penem dithiocarbamate derivatives as beta-lactamase inhibitors for use of antibacterial agents and antibiotics. EP 212404 (Cooke, et al.) describes 2-phenyl-2-penem-3-carboxylic acid derivatives as being antibacterial agents and antibiotics. WO 8700525 (Broom, et al.) describes 6-heterobicyclic-methylene-penem-3-carboxylic acid compounds which are both antibacterial and possess beta-lactamase inhibitory activities.
Thus, research activities to date in the area of retaining the activity of beta-lactam antibiotics have focused on efforts to neutralize or inactivate beta-lactamase enzymes after they are formed. There has been little or no attention directed to preventing the formation of beta-lactamase enzymes by any means.
Of course, the ability to inhibit the formation of beta-lactamase enzymes is extremely desirable as this process would permit a larger proportion of beta-lactam antibiotics to be effective, without interference from the beta-lactamase enzymes.